GATA2 deficiency: a long way to diagnosis (case report)



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Abstract

GATA2 deficiency is a form of inborn errors of immunity (or primary immunodeficiencies) with a wide range of symptoms. According to the international classification of primary immunodeficiency diseases it is classified as congenital defects of phagocyte number, function, or both. Heterozygous mutations in the GATA2 gene cause syndromes reported in the literature as dendritic cell, monocyte, B and NK lymphoid deficiency, MonoMAC syndrome (monocytopenia and mycobacterial infection), familial myelodysplastic syndrome, and Emberger syndrome (the combination of myelodysplasia and congenital lymphedema).

Here we present a literature review on GATA2 deficiency and report a clinical case of an adult woman with the abovementioned immune defect, the results of laboratory and instrumental examinations, therapy, and outcome. The patient’s condition was complicated by lymphedema, myelodysplastic syndrome, endometrial carcinoma in situ, nonspecific pulmonary lesion, recurrent miscarriage, and rheumatic conditions (erythema nodosum). The mentioned diversity of clinical manifestations is a reason for long diagnostic search, as well as difficulties in diagnosis and selection of optimal treatment tactics.

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About the authors

Irina S. Avgustovskaya

Clinical City Hospital No. 52; The First Sechenov Moscow State Medical University (Sechenov University)

Author for correspondence.
Email: is-avgustovskaya@mail.ru
ORCID iD: 0009-0000-0043-5985

Moscow Center of Allergy and Immunology

Россия, Moscow; Moscow

Anna A. Roppelt

Clinical City Hospital No. 52

Email: roppelt_anna@mail.ru
ORCID iD: 0000-0001-5132-1267
SPIN-code: 7249-4423

MD, Cand. Sci. (Medicine)

Россия, Moscow

Ulyana A. Markina

Clinical City Hospital No. 52

Email: itcher.md@bk.ru
ORCID iD: 0000-0002-6646-4233

Moscow Center of Allergy and Immunology

Россия, Moscow

Anna L. Gogol

Clinical City Hospital No. 52

Email: catharsis17@yandex.ru
ORCID iD: 0009-0005-1988-1703
Россия, Moscow

Irina P. Beloglazova

Clinical City Hospital No. 52; The Russian National Research Medical University named after N.I. Pirogov

Email: beloglazova.irina@gmail.com
ORCID iD: 0000-0002-2266-1497
SPIN-code: 5339-8420

MD, Cand. Sci. (Medicine)

Россия, Moscow; Moscow

Vera V. Korennaya

Clinical City Hospital No. 52; Russian Medical Academy of Continuous Professional Education

Email: drkorennaya@mail.ru
ORCID iD: 0000-0003-1104-4415
SPIN-code: 9940-6413

MD, Cand. Sci. (Medicine), Assistant Professor

Россия, Moscow; Moscow

Alexander V. Karaulov

The First Sechenov Moscow State Medical University (Sechenov University)

Email: drkaraulov@mail.ru
ORCID iD: 0000-0002-1930-5424
SPIN-code: 4122-5565

MD, Dr. Sci. (Medicine), Professor

Россия, Moscow

Asel Yu. Nurtazina

The First Sechenov Moscow State Medical University (Sechenov University)

Email: asel26nurtazina@mail.ru
ORCID iD: 0000-0002-2337-3307
SPIN-code: 5028-4695

Cand. Sci. (Medicine), Assistant Professor

Россия, Moscow

Maryana A. Lysenko

Clinical City Hospital No. 52; The Russian National Research Medical University named after N.I. Pirogov

Email: gkb52@zdrav.mos.ru
ORCID iD: 0000-0001-6010-7975
SPIN-code: 3887-6250

MD, Dr. Sci. (Medicine), Professor

Россия, Moscow; Moscow

Darya S. Fomina

Clinical City Hospital No. 52; The First Sechenov Moscow State Medical University (Sechenov University); Astana Medical University

Email: daria_fomina@mail.ru
ORCID iD: 0000-0002-5083-6637
SPIN-code: 3023-4538

Moscow Center of Allergy and Immunology, MD, Cand. Sci. (Medicine), Assistant Professor

Россия, Moscow; Moscow; Astana, Kazakhstan

References

  1. Tangye SG, Al-Herz W, Bousfiha A, et al. Human inborn errors of immunity: 2022 update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473–1507. doi: 10.1007/s10875-022-01289-3
  2. Fabozzi F, Mastronuzzi A, Ceglie G, et al. GATA 2 deficiency: focus on immune system impairment. Front Immunol. 2022;13:865773. doi: 10.3389/fimmu.2022.865773
  3. Fabozzi F, Strocchio L, Mastronuzzi A, Merli P. GATA2 and marrow failure. Best Pract Res Clin Haematol. 2021;34(2):101278. doi: 10.1016/j.beha.2021.101278
  4. Dickinson RE, Griffin H, Bigley V, et al. Exome sequencing identifies GATA-2 mutation as the cause of dendritic cell, monocyte, B and NK lymphoid deficiency. Blood. 2011;118(10):2656–2658. doi: 10.1182/blood-2011-06-360313
  5. Ling KW, Ottersbach K, van Hamburg JP, et al. GATA-2 plays two functionally distinct roles during the ontogeny of hematopoietic stem cells. J Exp Med. 2004;200(7):871–882. doi: 10.1084/jem.20031556
  6. Koyunlar C, de Pater E. From basic biology to patient mutational spectra of GATA2 haploinsufficiencies: what are the mechanisms, hurdles, and prospects of genome editing for treatment. Front Genome Ed. 2020;2:602182. doi: 10.3389/fgeed.2020.602182
  7. Peters IJA, de Pater E, Zhang W. The role of GATA2 in adult hematopoiesis and cell fate determination. Front Cell Dev Biol. 2023;11:1250827. doi: 10.3389/fcell.2023.1250827
  8. Rodrigues NP, Boyd AS, Fugazza C, et al. GATA-2 regulates granulocyte-macrophage progenitor cell function. Blood. 2008;112(13):4862–4873. doi: 10.1182/blood-2008-01-136564
  9. Collin M, Dickinson R, Bigley V. Haematopoietic and immune defects associated with GATA2 mutation. Br J Haematol. 2015;169(2):173–187. doi: 10.1111/bjh.13317
  10. Wlodarski MW, Hirabayashi S, Pastor V, et al. Prevalence, clinical characteristics, and prognosis of GATA2-related myelodysplastic syndromes in children and adolescents. Blood. 2016;127(11):1387–1518. doi: 10.1182/blood-2015-09-669937
  11. Calvo KR, Hickstein DD. The spectrum of GATA2 deficiency syndrome. Blood. 2023;141(13):1524–1532. doi: 10.1182/blood.2022017764
  12. Spinner MA, Sanchez LA, Hsu AP, et al. GATA2 deficiency: a protean disorder of hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809–821. doi: 10.1182/blood-2013-07-515528
  13. Homan CC, Venugopal P, Arts P, et al. GATA2 deficiency syndrome: a decade of discovery. Hum Mutat. 2021;42(11):1399–1421. doi: 10.1002/humu.24271
  14. Mace EM, Hsu AP, Monaco-Shawver L, et al. Mutations in GATA2 cause human NK cell deficiency with specific loss of the CD56(bright) subset. Blood. 2013;121(14):2669–2677. doi: 10.1182/blood-2012-09-453969
  15. Johnson KD, Hsu AP, Ryu MJ, et al. Cis-element mutated in GATA2-dependent immunodeficiency governs hematopoiesis and vascular integrity. J Clin Invest. 2012;122(10):3692–3704. doi: 10.1172/JCI61623
  16. Dancy E, Stratton P, Pichard DC, et al. Human papillomavirus disease in GATA2 deficiency: a genetic predisposition to HPV-associated female anogenital malignancy. Front Immunol. 2024;15:1445711. doi: 10.3389/fimmu.2024.1445711
  17. Pasquet M, Bellanné-Chantelot C, Tavitian S, et al. High frequency of GATA2 mutations in patients with mild chronic neutropenia evolving to MonoMac syndrome, myelodysplasia, and acute myeloid leukemia. Blood. 2013;121(5):822–829. doi: 10.1182/blood-2012-08-447367
  18. Maciejewski-Duval A, Meuris F, Bignon A, et al. Altered chemotactic response to CXCL12 in patients carrying GATA2 mutations. J Leukoc Biol. 2016;99(6):1065–1076. doi: 10.1189/jlb.5MA0815-388R
  19. Fujiwara T. GATA transcription factors: basic principles and related human disorders. Tohoku J Exp Med. 2017;242(2):83–91. doi: 10.1620/tjem.242.83
  20. Raziq FI, Abubaker A, Smith E, Uddin M. Secondary pulmonary alveolar proteinosis in GATA-2 deficiency (MonoMAC syndrome). BMJ Case Rep. 2020;13(11):e238290. doi: 10.1136/bcr-2020-238290
  21. Ostergaard P, Simpson MA, Connell FC, et al. Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome). Nat Genet. 2011;43(10):929–931. doi: 10.1038/ng.923
  22. Østergård S, Vorbeck CS, Meinert M. [Vulvar intraepithelial neoplasia]. Ugeskr Laeger. 2018;180(20):V12170931. [In Danish].
  23. Selitsky SR, Marron D, Mose LE, et al. Epstein–Barr virus-positive cancers show altered B-cell clonality. mSystems. 2018;3(5):e00081-18. doi: 10.1128/mSystems.00081-18
  24. Cohen JI, Dropulic L, Hsu AP, et al. Association of GATA2 deficiency with severe primary Epstein–Barr virus (EBV) infection and EBV-associated cancers. Clin Infect Dis. 2016;63(1):41–47. doi: 10.1093/cid/ciw160
  25. Kazenwadel J, Secker GA, Liu YJ, et al. Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature. Blood. 2012;119(5):1283–1291. doi: 10.1182/blood-2011-08-374363
  26. Mammoto A, Connor KM, Mammoto T, et al. A mechanosensitive transcriptional mechanism that controls angiogenesis. Nature. 2009;457(7233):1103–1108. doi: 10.1038/nature07765
  27. Amarnani AA, Poladian KR, Marciano BE, et al. A panoply of rheumatological manifestations in patients with GATA2 deficiency. Sci Rep. 2020;10(1):8305. doi: 10.1038/s41598-020-64852-1
  28. Frolov EA, Abdulaeva FI, Gornostaeva UA, et al. Features of the clinical picture and course of GATA2 deficiency complicated by generalized verrucosis with an outcome in myelodysplastic syndrome in adulthood. Medical Herald of the South of Russia. 2023;14(4):35–43. (In Russ). doi: 10.21886/2219-8075-2023-14-4-35-43
  29. Basheer A, Padrao EMH, Huh K, et al. Pulmonary alveolar proteinosis due to familial myelodysplastic syndrome with resolution after stem cell transplant. Autops Case Rep. 2022;12:e2021382. doi: 10.4322/acr.2021.382
  30. Maeurer M, Magalhaes I, Andersson J, et al. Allogeneic hematopoietic cell transplantation for GATA2 deficiency in a patient with disseminated human papillomavirus disease. Transplantation. 2014;98(12):e95–e96. doi: 10.1097/TP.0000000000000520
  31. Parta M, Cole K, Avila D, et al. Hematopoietic cell transplantation and outcomes related to human papillomavirus disease in GATA2 deficiency. Transplant Cell Ther. 2021;27(5):435.e1–435.e11. doi: 10.1016/j.jtct.2020.12.028
  32. De Witte T, Bowen D, Robin M, et al. Allogeneic hematopoietic stem cell transplantation for MDS and CMML: recommendations from an international expert panel. Blood. 2017;129(13):1753–1762. doi: 10.1182/blood-2016-06-724500
  33. Bortnick R, Wlodarski M, de Haas V, et al. Hematopoietic stem cell transplantation in children and adolescents with GATA2-related myelodysplastic syndrome. Bone Marrow Transplant. 2021;56(11):2732–2741. doi: 10.1038/s41409-021-01374-y
  34. Nichols-Vinueza DX, Parta M, Shah NN, et al. Donor source and post-transplantation cyclophosphamide influence outcome in allogeneic stem cell transplantation for GATA2 deficiency. Br J Haematol. 2022;196(1):169–178. doi: 10.1111/bjh.17840
  35. Parta M, Shah NN, Baird K, et al. Allogeneic hematopoietic stem cell transplantation for GATA2 deficiency using a busulfan-based regimen. Biol Blood Marrow Transplant. 2018;24(6):1250–1259. doi: 10.1016/j.bbmt.2018.01.030
  36. Hofmann I, Avagyan S, Stetson A, et al. Comparison of outcomes of myeloablative allogeneic stem cell transplantation for pediatric patients with bone marrow failure, myelodysplastic syndrome and acute myeloid leukemia with and without germline GATA2 mutations. Biol Blood Marrow Transplant. 2020;26(6):1124–1130. doi: 10.1016/j.bbmt.2020.02.015
  37. Tichelli A, Rovó A. Fertility issues following hematopoietic stem cell transplantation. Expert Rev Hematol. 2013;6(4):375–388. doi: 10.1586/17474086.2013.816507
  38. Skvortsova YuV, Papusha LI, Rudneva AE, et al. Pathology of the reproductive system after allogeneic hematopoietic stem cell transplantation in children: a single center experience. Russian Journal of Hematology and Transfusiology. 2017;62(3):124–134. (In Russ). doi: 10.18821/0234-5730-2017-62-3-124-134

Supplementary files

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2. Fig. 1. Pathogenesis of the main clinical manifestations of GATA2 deficiency.

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3. Fig. 2. Computed tomography of the patient’s thoracic organs (dynamic observation). Interstitial changes persist in both lungs in the form of thickening of the interlobular and intralobular interstitium, more prominent in the apices.

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4. Fig. 3. The patient’s family tree. Note. wt – wild type; ? – genetic testing not performed; arrow – the patient.

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